Scientists at St. Jude Children's Research Hospital have discovered an approach similar to car-washing that prevents the accumulation of toxic proteins associated with Alzheimer's disease. The report was recently published in the journal of Cell.
Alzheimer's disease has become the sixth leading cause of death in the United States. This study in the mouse model of Alzheimer's disease provides a possible new approach to the treatment of this chronic neurodegenerative disease. This newly discovered pathway also helps to regulate inflammation, which makes it possible to release an immune response against a malignant brain tumor.
Researchers refer to this pathway as LC3-related endocytosis or LANDO. They found this pathway in microglia of the brain and central nervous system. However, prima facie evidence suggests that LANDO is a fundamental process in which all systemic cells function. The researchers found that LANDO can prevent neurotoxic β-amyloid protein precipitation in mice. Activation of this pathway can also prevent toxic neuroinflammation and neurodegeneration, including memory problems.
"In the context of neurodegenerative diseases such as Alzheimer's disease, activation of LANDO in microglia can produce therapeutic effects by enhancing the clearance of beta-amyloid proteins and neuroinflammation." said by the study author, St. Jude Dr. Douglas Green, Head of the Department of Immunology at the Children's Research Hospital.
Although the activation of LANDO seems to prevent neurodegenerative diseases, Dr. Bradlee Heckmann, Ph.D., the lead author of Green Labs, said that inhibition of the LANDO pathway may improve the effectiveness of cancer immunotherapy. "Although at an early stage, preliminary data using a primary brain tumor model suggests that inhibition of LANDO may provide a mechanism to activate inflammation in the tumor microenvironment, resulting in an anti-tumor response," Heckmann said.
The accumulation of β-amyloid protein in neurons is a feature of Alzheimer's disease. Scientists know that microglia can take up beta-amyloid proteins. The discovery of the LANDO pathway reveals what will happen next.
Heckmann likens LANDO to the operator of an automatic car wash machine. In this case, the car is a receptor on the microglia that binds to the neurotoxic β-amyloid protein and can carry the protein into the car wash. Then, just as the car is washed back to the street, when the β-amyloid protein is processed, the surface receptors return to the surface of the microglia, and additional beta-amyloid protein can be attached.
The automatic car wash system relies on hardware to secure the car to a track that passes through the machine. Similarly, LANDO requires several proteins to function. Proteins - rubicon, Beclin 1, ATG5 and atg7 - are more well known that they play a role in a related cellular pathway that is used to recover unwanted cellular components. The expression of these proteins will gradually decrease with the growth of age.
"You never know where science will go," Green said. "This project started because we were studying the immune response against cancer. Brad realized that these findings are related to a disease, but not to children, but to the elderly. This is how the science works. When you follow the data, you never know where it will lead."
Bradlee L. Heckmann et al. LC3-Associated Endocytosis Facilitates β-Amyloid Clearance and Mitigates Neurodegeneration in Murine Alzheimer's Disease. Cell (2019). DOI： 10.1016/j.cell.2019.05.056